BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.

Cadherins in neural crest cell development and transformation.

Cadherins constitute a superfamily of cell adhesion molecules involved in cell-cell interaction, histogenesis and cellular transformation. They have been implicated in the development of various lineages, including derivatives of the neural crest. Neural crest cells (NCC) emerge from the dorsal part of the neural tube after an epithelio-mesenchymal transition (EMT) and migrate through the embryo. After homing and differentiation, NCC give rise to many cell types, such as neurons, Schwann cells and melanocytes. During these steps, the pattern of expression of the various cadherins studied is very dynamic. Cadherins also display plasticity of expression during the transformation of neural crest cell derivatives. Here, we review the pattern of expression and the role of the main cadherins involved in the development and transformation of neural crest cell derivatives.

Pax3 acts cell autonomously in the neural tube and somites by controlling cell surface properties.

Pax3 is a member of the paired-box-containing transcription factors. It is expressed in the developing somites, dorsal spinal cord, mesencephalon and neural crest derivatives. Several loss-of-function mutations are correlated with the Splotch phenotype in mice and Waardenburg syndrome in humans. Malformations include a lack of muscle in the limb, a failure of neural tube closure and dysgenesis of numerous neural crest derivatives. In this study we have used embryonic stem (ES) cells to generate a lacZ knock-in into the Pax3 locus. The Pax3 knock-in Splotch allele (Sp(2G)) was used to generate Pax3-deficient ES cells in order to investigate whether, in chimeric embryos, Pax3 is acting cell autonomously in the somites and the neural tube. We found that while Pax3 function is essential for the neuroepithelium and somites, a wild-type environment rescues mutant neural crest cells. In the two affected embryonic tissues, mutant and wild-type cells undergo segregation and do not intermingle. The contribution of mutant cells to the neural tube and the somites displayed temporal differences. All chimeric embryos showed a remarkable contribution of blue cells to the neural tube at all stages analyzed, indicating that the Pax3-deficient cells are not excluded from the neural epithelium while development proceeds. In contrast, this is not true for the paraxial mesoderm. The somite contribution of Pax3(-/-) ES cells becomes less frequent in older embryos as compared to controls with Pax3(+/-) ES cells. We propose that although Pax3 function is related to cell surface properties, its role may differ in various tissues. In fact, apoptosis was found in Pax3-deficient cells of the lateral dermomyotome but not in the neural tube.

A novel model to study the dorsolateral migration of melanoblasts.

Melanocytes derived from pluripotent neural crest cells migrate initially in the dorsolateral pathway between the ectoderm and dermomyotome. To understand the role of specific proteins involved in this cell migration, we looked for a cellular model that mimics the in vivo behavior of melanoblasts, and that allows functional studies of their migration. We report here that wild-type embryonic stem (ES) cells are able to follow the ventral and dorsolateral neural crest pathways after being grafted into chicken embryos. By contrast, a mutant ES cell line deficient for beta1 integrin subunits, proteins involved in cell-extracellular interactions, had a severely impaired migratory behavior. Interestingly, ES cells deficient for Kit, the tyrosine kinase receptor for the stem cell factor (SCF), behaved similarly to wild-type ES cells. Thus, grafting mouse ES cells into chicken embryos provides a new cellular system that allows both in vitro and in vivo studies of the molecular mechanisms controlling dorsolateral migration.

Expression of the cytoplasmic domain of E-cadherin induces precocious mammary epithelial alveolar formation and affects cell polarity and cell-matrix integrity.

Cadherins are cell adhesion molecules involved in cell-cell adhesion, signalling, and cellular proliferation and differentiation. E-cadherin is required for the formation of epithelium in vivo. We investigated the contribution of the cytoplasmic domain of E-cadherin to adhesion, signalling, and differentiation during murine mammary gland development, by in vivo expression of a gene encoding a truncated form of E-cadherin lacking the extracellular domain. The expression of this gene in mammary epithelial cells during pregnancy induced precocious lobular epithelial morphogenesis associated with morphological differentiation and the early synthesis of various molecules (advanced milk fat globule appearance and milk protein production). After delivery, when a fully differentiated and secretory epithelium is required for lactation, the cytoplasmic domain of E-cadherin had a dominant-negative effect on cell-cell adhesion and affected the structure and function of the epithelium. This also led to the partial loss of epithelial polarisation and changes in the basement membrane, both important in malignancy. Thus, the cytoplasmic domain of E-cadherin induces epithelial morphogenesis, but also alters the cohesiveness of the fully differentiated epithelium.

[Standard versus decreasing weight loss. Better tolerance and comfort in hemodialysis]. / Pérdida standard vs. pérdida decreciente. Mejor tolerancia y confort en hemodiálisis.

The usual procedure to eliminate an overweight in hemodialysis consist in eliminating the whole amount of water distributed in an equitable way during the four hours hemodialysis session. This approach has tried to establish in what way the comfort of patients under dialysis improved, varying this loss in a decreasing way from the beginning to the end of the session.